51: GDF5 Activates Smad1/5/8-Akt Signaling to Attenuate Trigeminal Neuralgia-Related Pain

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Neuroimmunology, Drug development

Background and Aims: Growth differentiation factor 5 (GDF5), a prominent member of the bone morphogenetic protein family, has demonstrated significant potential in promoting neural repair and maintaining myelin integrity. However, its therapeutic relevance in trigeminal neuralgia (TN) remains largely unexplored. This study investigated whether GDF5 exerts protective effects against demyelination and mechanical hypersensitivity in a rat model of TN, alongside its underlying molecular mechanisms.

Methods: A rat model of TN was established using chronic constriction injury of the infraorbital nerve (ION-CCI). Recombinant adeno-associated viruses (AAVs) were employed for the localized modulation of GDF5 expression within the trigeminal spinal subnucleus caudalis (VC). Nociceptive behaviors were evaluated via mechanical withdrawal thresholds (MWT) using Von Frey filaments. The integrity of myelin and the survival of oligodendrocytes (OLs) were assessed through transmission electron microscopy, immunofluorescence, and Western blotting.

Results: ION-CCI triggered profound mechanical allodynia, accompanied by extensive demyelination and a significant reduction in both GDF5 expression and OL density in the VC. Viral-mediated knockdown of GDF5 (sh-GDF5) in naive rats effectively mimicked the TN phenotype, inducing spontaneous mechanical hypersensitivity and OL loss. Conversely, AAV-mediated GDF5 overexpression significantly attenuated ION-CCI-induced pain behaviors and preserved myelin structure by inhibiting OL apoptosis. Mechanistically, GDF5 deficiency was associated with the suppression of the Smad1/5/8-Akt signaling axis. Restoration of GDF5 levels successfully reactivated the Smad1/5/8 phosphorylation and upregulated downstream anti-apoptotic proteins (such as Bcl-2), thereby enhancing OL survival under chronic nerve injury.

Conclusions: Our findings demonstrate that GDF5 plays a pivotal role in maintaining the myelin microenvironment in the VC. GDF5 alleviates TN-associated pain by preventing oligodendrocyte apoptosis and subsequent demyelination through the activation of the Smad1/5/8-Akt signaling pathway. These results suggest that GDF5 may serve as a promising neuroprotective candidate for the clinical management of trigeminal neuralgia.

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Presenting Author: Tao Liu
Submitting Author: Tao Liu

Senior Author: Hui Li

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Tao Liu - The Second Xiangya Hospital of Central South University
• Xuemei Miao - The Second Xiangya Hospital of Central South University
• Hui Li - The Second Xiangya Hospital of Central South University